Maternal substance use disorders are a substantial public health concern and the neurological consequences of prenatal exposure are a major threat to the long-term health of offspring. Globally, prevalence of Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Spectrum Disorders (FASD) is between 2-7 and 20-50 per 1000, respectively. By contrast, in certain high-risk communities in South Africa, prevalence is reported to be as high as 63 and 155 per 1000, respectively. Though prenatal alcohol exposure (PAE) is known to affect the central nervous system, to date, little data exists in respect of the impact of PAE in early childhood, before both higher-level brain networks are established and other potentially confounding post- natal environmental influences have come into play. For neurodevelopmental disorders, studies have consistently shown that early intervention, based on detection and targeted interventions, leads to better long-term outcomes. We aim to address this precise gap in knowledge by imaging the brain and 3D face across the FASD continuum to investigate early biomarkers, trajectories and functional correlates of PAE in a cohort followed prospectively from birth to age 6 years. Data: Our cohort includes a well characterized subsample of children (PAE and healthy controls) enrolled in the Drakenstein Child Health Study in Cape Town, South Africa, who have been scanned as neonates and at 2-3 years of age. Preliminary published data shows highly significant relationships between PAE and regional gray and white matter changes, already discernible in newborns, well before the age FASD is typically diagnosed. An additional longitudinal assessment at 6-years will yield a unique FASD sample with 3 distinct time points (infants, toddlers and children), allowing characterization of brain and face morphology and brain structure and function in this previously understudied early developmental period. This proposal addresses fundamental gaps concerning the presence, timing and regional specificity of altered brain morphology and structural and functional connectivity in association with the effects of PAE on the developing brain from birth to 6 years, and the relationships with facial dysmorphology. The research team has successfully gathered data from the proposed cohort as neonates and at 2?3 years of age. The benefits of extending this research to a subsequent imaging time-point, with a larger range of developmental and neurobehavioral assessments, provides an unprecedented opportunity to determine longitudinal effects of PAE on the trajectory of the developing brain in these critical early years, the links between neural and face predictors of PAE and the long-term clinical significance of these findings. This research will illuminate early neurodevelopmental mechanisms leading to subsequent behavioral and neurological disturbances, which may allow opportunities for targeting interventions when brain plasticity is still relatively fluid. This project might also lead to new strategies for early diagnosis using both face and brain biomarkers.